Inhibitors of dipeptidyl peptidase I

a technology of dipeptides and inhibitors, applied in the direction of peptide sources, peptide/protein ingredients, drug compositions, etc., can solve the problems of rapid intramolecular decomposition and n-terminal unprotected dipeptide derivatives, and achieve the effect of improving the wound healing process

Inactive Publication Date: 2005-01-18
VIVORYON THERAPEUTICS NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, N-terminally unprotected dipeptide derivatives tend towards rapid, intramolecular decomposition.

Method used

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  • Inhibitors of dipeptidyl peptidase I
  • Inhibitors of dipeptidyl peptidase I
  • Inhibitors of dipeptidyl peptidase I

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of TFA*H-Gly-L-Phe-NHO-Ac (10)

TFA*H-Gly-L-Phe-NHO-Ac (10) was prepared according to Method D. The compound was purified by flash chromatography to give the product as a white solid (93%) of m.p. 71-73° C.—TLC (n-BuOH / ethyl acetate / water / acetic acid, 1:1:1:1): Rf=0.73.—1H NMR (400 MHz, DMSO-d6): δ=2.16 (s, 3H, CH3), 2.80 (dd, 1H, J=14.0 Hz, J=9.7 Hz, CH2 Phe), 3.04 (dd, 1H, J=13.9 Hz, J=9.6 Hz, CH2 Phe), 3.40 (d, 1H, J=16.3 Hz, CH2 Gly), 3.55 (d, 1H, J=16.3 Hz, CH2 Gly), 4.58-4.64 (m, 1H, CH Phe), 7.19-7.30 (m, 5H, aryl-H), 8.84 (d, 1H, J=8.4 Hz, NH).—MS (EI) m / z (%): 280 [M+H+].

example 2

Synthesis of TFA*H-Gly-L-Phe-NHO-Bz (11)

TFA*H-Gly-L-Phe-NHO-Bz (11) was prepared according to Method D. The compound was purified by flash chromatography to give the product as a white solid (66%) of m.p. 75-80° C.—TLC (n-BuOH / ethyl acetate / water / acetic acid, 1:1:1:1): Rf=0.81.—1H NMR (500 MHz, DMSO-d6): δ=2.86 (dd, 1H, J=13.9 Hz, J=10.0 Hz, CH2 Phe), 3.13 (dd, 1H, J=13.9 Hz, J=9.9 Hz, CH2 Phe), 3.43 (d, 1H, J=16.3 Hz, CH2 Gly), 3.58 (d, 1H, J=16.3 Hz, CH2 Gly), 4.68-4.72 (m, 1H, CH Phe), 7.21-7.25 (m, 1H, aryl-H), 7.26-7.31 (m, 4H, aryl-H), 7.58-7.63 (m, 2H, aryl-H), 7.74-7.77 (m, 1H, aryl-H), 7.93-8.03 (m, 2H, aryl-H), 7.94 (s, br., 3H, NH3+), 8.91 (d, 1H, J=8.3 Hz, NH), 12.46 (s, br., 1H, NH).—MS (EI) m / z (%): 342 [M+H+].

example 3

Synthesis of TFA*H-Gly-L-Phe-NHO-Bz-p-CH3 (12)

TFA*H-Gly-L-Phe-NHO-Bz-p-CH3 (12) was prepared according to Method D. The compound was purified by flash chromatography to give the product as a white solid (82%) of m.p. 98-101° C.—TLC (n-BuOH / ethyl acetate / water / acetic acid, 1:1:1:1): Rf=0.75.—1H NMR (400 MHz, DMSO-d6): δ=2.41 (s, 3H, CH3), 2.85 (dd, 1H, J=13.7 Hz, J=10.0 Hz, CH2 Phe), 3.12 (dd, 1H, J=12.9 Hz, J=10.0 Hz, CH2 Phe), 3.42 (d, 1H, J=15.8 Hz, CH2 Gly), 3.58 (d, 1H, J=16.0 Hz, CH2 Gly), 4.66-4.72 (m, 1H, CH Phe), 7.21-7.25 (m, 1H, aryl-H), 7.27-7.31 (m, 4H, aryl-H), 7.40 (d, 2H, J=8.0 Hz, aryl-H), 7.90 (d, 2H, J=8.2 Hz, aryl-H), 7.94 (s, br., 3H, NH3+), 8.90 (d, 1H, J=8.4 Hz, NH), 12.40 (s, br., 1H, NH).—MS (EI) m / z (%): 356 [M+H+].

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Abstract

The present invention relates to specific inhibitors of the cysteine protease dipeptidyl peptidase I (DP I), which can be used in the treatment of malignant cell degeneration, immune deseases impaired wound healing and metabolic diseases of humans and are represented by the general formula in which R is a peptide or a branched or unbranched C1-C9 alkyl chain, a branched or unbranched C2-C9 alkenyl chain, a branched or unbranched C2-C9 alkynyl chain, a C3-C9 cycloalkyl, C4-C9 carbocyclic, C5-C14 aryl, C3-C9 heteroaryl, C3-C9 heterocyclic, all of the above residues optionally being substituted, the residue AS—AS is a dipeptide or a mimetic thereof, AS is an amino acid or a peptide mimetic thereof. The amino acid is peptide bound with R and R′ is a branched or unbranched C1-C9 alkyl chain, a branched or unbranched C2-C9 alkenyl chain, a branched or unbranched C2-C9 alkynyl chain, a C3-C9 cycloalkyl, C4-C9 cycloalkenyl, C2-C9 heterocycloalkyl, C3-C9 heterocycloalkenyl, C5-C14 aryl, C3-C9 heteroaryl, C3-C9 heterocyclic, whereas the heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocyclic residue can have up to 6 hetero ring atoms, an amino acid or a peptide mimetic thereof, all of the above residues may be optionally substituted, or is H.

Description

FIELD OF THE INVENTIONThe present invention relates to compounds that act as specific inhibitors of the cysteine protease dipeptidyl peptidase I (DP I). Compounds based on acylated hydroxamates are distinguished by being chemically stable in aqueous solutions, including biological fluids (Brömme & Demuth, 1994). Acylated hydroxamates are suicide inhibitors which deactivate the DP I by the reaction with the nucleophilic active site thiol residue.BACKGROUND OF INVENTIONDipeptidyl peptidase I is known to release active granulocyte serine proteases of lymphatic cells from their pro-forms. It participates in mechanisms that are used physiologically by cytotoxic lymphocytes in immune defence. In the case of pathophysiological processes such as malignant transformations of myeloid and lymphatic cells, the suppression of such mechanisms can be used for the treatment of carcinomas, immune diseases or metabolic diseases. The inhibitors of DP I according to the invention can be used for the tr...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K5/00C07K5/06
CPCC07K5/06026C07K5/06
Inventor NIESTROJ, ANDREHEISER, ULRICHDEMUTH, HANS-ULRICH
Owner VIVORYON THERAPEUTICS NV
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